Quantitative Biosciences Dissertation Proposal
School of Physics
Thesis Advisors: Dr. Jennifer Curtis and Dr. Shuyi Nie
Open to the Community
The Biomechanical Role of Hyaluronan in Cell Migration
Van Leer Electrical and Computer Engineering Building
777 Atlantic Dr. NW, Room E361
Dr. Andres Garcia; School of Mechanical Engineering; Georgia Institute of Technology
Dr. Khalid Salaita; Department of Chemistry; Emory University
Dr. Denis Tsygankov; School of Biomedical Engineering; Georgia Institute of Technology
Cell migration is critical to numerous fundamental biological processes throughout the lifespan of multicellular organisms, including embryonic development, homeostasis, wound healing, and disease. Local changes in cell adhesion, such as coordinated attachment and detachment events, help regulate the movement of migrating cells, together with other crucial factors. Considerable efforts have focused on integrin-mediated adhesion, and focal adhesions (FAs), the molecular assemblies that connect the cytoskeleton to the extracellular matrix (ECM), while carrying the mechanical load. However, very little attention has been given to ’bulky’ glycans and glycoproteins, found in the cell-ECM interface, which may mechanically alter cell adhesion and thereby modulate migration, in addition to, and independent of biochemical functions. Hyaluronan (HA), a giant polysaccharide decorated by bottlebrush-shaped proteoglycans (PGs), is often tethered to the cell-surface, forming a thick glycocalyx (GCX), both in vitro and in vivo. Several studies implicate HA as an important player in mediating cell adhesion. Further, in the domain of cell migration, the asymmetric distribution of HA-rich GCX on migrating cells is consistent with interpretation of facilitated differential adhesion, where compressed HA polymers in the back of the cell exert repulsive forces that locally weaken cell adhesion, and reduced polymer at front allow stronger adhesion. Yet, no systematic study is published in the literature.
Our long-term goal is to determine whether compressed HA-GCX which leads to repulsive forces, at the cell-ECM and cell-cell interfaces, is a fundamental strategy employed by living organisms to mechanically regulate tissue organization, repair, and disease. The objective of this thesis is to determine whether confined HA at the cell-ECM interface, mechanically regulates cell migration. Our central hypothesis is that HA mechanically regulates cell adhesion and thereby modulates migration. We have formulated this hypothesis based on our preliminary results, providing the first quantitative evidence that HA (1) weakens cell adhesion strength; (2) alters migration speed in predictable, adhesion dependent fashion; and based on our first fluorescently labeled asymmetric distribution of HA in cell-substratum interfaces of migrating cells, (3) may promote differential adhesion.
Our proposed research is innovative, because it addresses implications that have never been studied, regarding the MECHANICAL ROLE OF HA in cell adhesion and migration. The suggested work is different from current studies, in the systematic characterization of both REPULSIVE confined HA and ADHESIVE FAs, in different model systems in vitro, ex vivo, and in vivo. This thesis is expected to achieve the following milestones. First, we will determine whether interfacial HA mechanically decreases cell adhesion strength. Second, we will determine whether changes in cell adhesion strength and differential distribution through asymmetric distribution, mechanically regulates migration. Third, we will determine whether HA mechanically regulates migration in embryonic development. The data will fill a fundamental gap in our knowledge, addressing the mechanism of adhesion regulation, and provide insight into whether HA and FA complexes are complementary systems that co-orchestrate cell adhesion and migration. This work will be relevant to a large range of scientific disciplines and fields, from birth defects, to cancer biology, to tissue engineering, to wound healing.